10-114045046-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000684.3(ADRB1):c.914G>C(p.Arg305Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADRB1 NM_000684.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.60

Genes affected

ADRB1 (HGNC:285): (adrenoceptor beta 1) The adrenergic receptors (subtypes alpha 1, alpha 2, beta 1, and beta 2) are a prototypic family of guanine nucleotide binding regulatory protein-coupled receptors that mediate the physiological effects of the hormone epinephrine and the neurotransmitter norepinephrine. Beta-1 adrenoceptors are predominately located in the heart. Specific polymorphisms in this gene have been shown to affect the resting heart rate and can be involved in heart failure. [provided by RefSeq, Sep 2019]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADRB1	NM_000684.3	c.914G>C	p.Arg305Pro	missense_variant	1/1	ENST00000369295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADRB1	ENST00000369295.4	c.914G>C	p.Arg305Pro	missense_variant	1/1		NM_000684.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 06, 2023

The c.914G>C (p.R305P) alteration is located in exon 1 (coding exon 1) of the ADRB1 gene. This alteration results from a G to C substitution at nucleotide position 914, causing the arginine (R) at amino acid position 305 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
Cadd	Uncertain	24
Dann	Benign	0.90
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.41	T
MutationTaster	Benign	0.53	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.21
Sift	Benign	0.084	T
Sift4G	Benign	0.12	T
Vest4		0.17
MutPred		0.53		Loss of MoRF binding (P = 0.0031);
MVP		0.83
ClinPred		0.46	T
GERP RS		3.9
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1271293827; hg19: chr10-115804805;